Spaeth, JasonMolina, Carmella EvansKanojia, SukratiLinnemann, Amelia K.Mastracci, TeresaElmendorf, Jeffrey S.2024-09-112024-09-112024-08https://hdl.handle.net/1805/43258IUIPancreatic β cells are integral in synthesizing, packaging, and secreting insulin, crucial for maintaining blood glucose homeostasis. However, in diabetic conditions, some β cells lose function of transcription factors (TFs), which drive expression of genes critical for insulin secretion. Among these, PDX1 plays a vital role in pancreas development and mature β cell function. The activity of PDX1 is modulated by coregulators like the SWI/SNF chromatin remodeling and Nucleosome Remodeling and Deacetylase (NuRD) complexes. Our study unveils a novel interacting partner of PDX1, the Staphylococcal Nuclease and Tudor domain-containing protein (SND1), known for its role in facilitating protein-protein interactions and transcriptional control across tissues. Confirming PDX1:SND1 interactions in rodent and human β cells, we employed CRISPR-Cas9 to delete Snd1, revealing altered gene expression associated with insulin secretion and cell proliferation, which were confirmed through functional analyses, highlighting the importance of SND1 in β cell function. Notably, PDX1:SND1 interactions were reduced in human β cells from type 2 diabetes (T2D) donors, indicating its role in diabetes pathogenesis. Additionally, our investigation into the NuRD complex discovered interactions between PDX1 and CHD4, a helicase within the complex, are crucial for modulating PDX1 transcriptional activity in β cells. Deletion of Chd4 led to increased CHD3 protein levels, prompting us to explore the role of CHD3 in compensating for loss of CHD4. β cell specific-inducible deletion of Chd3 alone did not impact glucose homeostasis, whereas concurrent deletion of Chd3 and Chd4 resulted in severe glucose intolerance, reduced β cell mass, and compromised insulin release. Loss of both subunits led to β cell dysfunction and loss of identity, emphasizing the compensatory role of CHD3. Future investigations will evaluate gene expression and chromatin accessibility changes in Chd3/Chd4-deficient β cells, along with assessing the impact of diabetes on PDX1:CHD3 interactions in T2D human donor tissues.en-USdiabetesislet biologyNuRD complexpancreas biologypdx1type 2 diabetesThesis